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Therapeutic Roles of Phenolic

Antioxidants in Herbal Medicine
September 2022
In book: Health Benefits of Phenolic Antioxidants (pp.135) ·
Publisher: Nova Science Publishers, Inc. New York

Authors:

John Onyebuchi Ogbodo

University of Nigeria

Chinazom P Agbo
University of Nigeria

Adaeze Echezona
University of Nigeria

Tobechukwu Christian Ezike

University of Nigeria

Show all 8 authors

References (148) Figures (5)

Abstract and Figures

Herbal medicine is still the alternative source of medical

treatment globally. Herbs are the different parts of a plant
(seed, leave, root, and stem/bark) traditionally used for
their therapeutic value. They are utilized in traditional
medicine for the treatment of various illness and diseases.
The potential medicinal value of herbal medicines is as a
result of the naturally occurring phytochemicals (including
phenol) therein with therapeutic properties. The World
Health Organizations’ (WHO) primary concern centers on
the safety, potency and efficacy of these widely consumed
herbal products. Generally, though herbal remedies have
fewer side effects compared to conventional drugs due to
their near organic form, some have proven to pose some
adverse effects following consumption, which among
others are related to the presence of contaminants
introduced during processing. Also, self-medication,
unqualified practitioners, substandard products, and
abnormal dosage delivery are some of the major risk
factors of herbal toxicity. These can be minimized in some
ways, including adherence to the herbal regulatory model,
use of efficient extraction methods, checkmate on the use
of adulterated synthetic ingredients, improve and
harmonization of regulatory and monitoring body. This
work aims to review some key plant phytochemicals
(including phenol), their safety and efficacy as it relates to
the factors stated above.

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Chapter 8

Therapeutic Role of Phenolic Antioxidants in

Herbal Medicine

John Onyebuchi Ogbodo1, Chinazom Precious Agbo2,

Adaeze Chidiebere Echezona2, Tobechukwu Christian Ezike3,
Stephen Chijioke Emencheta4,, Oluebube Chisom Onyia2,
Tochukwu Chisom Iguh5 and Stella Amarachi Ihim6

1Department
of Science Laboratory Technology, University of Nigeria, Nsukka, Nigeria
2Department
of Pharmaceutics, University of Nigeria, Nsukka, Nigeria
3Department
of Biochemistry, University of Nigeria, Nsukka, Nigeria
4Department of Pharmaceutical Microbiology and Biotechnology, University of Nigeria, Nsukka, Nigeria
5Department of Plant Science and Biotechnology, University of Nigeria, Nsukka, Nigeria
6Department of Pharmacology and Toxicology, University of Nigeria, Nsukka, Nigeria

Abstract

Herbal medicine is still the alternative source of medical treatment globally. Herbs are the
different parts of a plant (seed, leave, root, and stem/bark) traditionally used for their
therapeutic value. They are utilized in traditional medicine for the treatment of various
illness and diseases. The potential medicinal value of herbal medicines is as a result of
the naturally occurring phytochemicals (including phenol) therein with therapeutic
properties. The World Health Organizations’ (WHO) primary concern centers on the
safety, potency and efficacy of these widely consumed herbal products. Generally,
though herbal remedies have fewer side effects compared to conventional drugs due to
their near organic form, some have proven to pose some adverse effects following
consumption, which among others are related to the presence of contaminants introduced
during processing. Also, self-medication, unqualified practitioners, substandard products,
and abnormal dosage delivery are some of the major risk factors of herbal toxicity. These
can be minimized in some ways, including adherence to the herbal regulatory model, use
of efficient extraction methods, checkmate on the use of adulterated synthetic ingredients,
improve and harmonization of regulatory and monitoring body. This work aims to review
some key plant phytochemicals (including phenol), their safety and efficacy as it relates
to the factors stated above.

Keywords: phytochemicals, phenol, efficacy, safety, regulation


Corresponding Author’s Email: stephen.emencheta@unn.edu.ng.

2 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

1. Introduction

The therapeutic role of herbal remedies in treating different range of health disorder cannot be
over emphasized. In spite of the prevailing usage of synthetic drugs, herbal medicine still
maintains its key role in primary health management (Srirama et al., 2017). Poverty and lack
of access to synthetic drugs have made population of people in the developing nation like
Nigeria to depend on herbal remedy as primary sources of health care (Ribeirao, 2000).
Medicinal plants are thought to possess good medical potentials. However, the simultaneous
use of herbs with orthodox medicine has raised concerns in health care especially with
regards to drug-herb interaction (Kuhn, 2002). The use of traditional herbal medicines (THM)
began as the earliest form of disease management in the African continent during the Stone
Age but the advent of modern medicine and the understanding of disease pathogenesis
dwindled the popularity and utilization of herbs and traditional medicine in the treatment of
diseases (Evans et al. 2018). Nonetheless, the prominence of orthodox medicine. Although
orthodox medicines and synthetic drugs are chemically pure substances that are the primary
choice for treatment of diseases, the popularity of herbal medicines continues to grow all over
the world. About 80% of the African populations favours herbal medicine over synthetic
drugs for their primary health care needs (WHO, 2002).
Herbal medicines (HM) which is synonymous with African traditional medicines is also
called phyto-medicines or vegetable medicines (Mahomoodally, 2013). They includes herbs,
herbal extracts, and finished products containing plant parts and plant materials that are
intended for therapeutic purposes (WHO, 2001). Plant parts used in herbal medicine may
include roots, bulbs, tubers, barks, Rhizomes, leaves, stems, fruits, seeds, gums, nectars or
exudates. Although herbs are promoted as natural and harmless, recent studies indicate that
herbal supplements are associated with adverse effects (Manoj et al. 2014) and there is still a
gap in understanding the efficacy and safety of herbal remedies. When natural products or
herbs are administered concurrently with drugs, the overall bioavailability, pharmacokinetics,
pharmacodynamics and therapeutic effect of the drug may become altered. In addition, both
desirable and undesirable pharmacological effects often result from these interactions
between herbal products and drugs when administered (Neustadt, 2006). In the same vein,
interactions between synthetic drug and herbs may be potentially beneficial. A drug
interaction is simply an interaction between a drug and another substance that prevents the
drug from performing as originally expected or intended results (Zhao et al. 2011).

2. Phytochemicals

Phytochemicals are non-nutritive natural occurring plant chemicals which are protective or
preventive components of plant against disease (Deepak et al. 2016). Plants were traditionally
used for treatments even without knowing that the key preventive or protective mechanisms
lies in the phytochemicals contained in the Plants (Siti et al. 2021). Phytochemicals are made
up of series of naturally occurring bioactive compounds such as phenols, alkaloids,
flavonoids, carbohydrates, terpenoids, lipids etc. that interacts with the different components
of the living organisms to boast the body molecular system to fight diseases (Amiot et al.
2021). Plant bioactive components are the secret of the positive effects of herbal medication

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 3

(Barani et al. 2021). These naturally occurring phytochemicals (secondary metabolites) such
as alkaloids, phenols, flavonoids, terpenoids etc. exhibit a wide range of therapeutic potentials
against diverse types of diseases (Tolve et al. 2020).

2.1. Phenolic Compounds

This the most abundant class of plant secondary metabolites synthesized by plant for its
survival (Jin et al. 2010). They are derivatives of ringed aromatic compound which can be
classified as phenolic acid (single ring) or polyphenolics (many rings) (Tsao, 2010). This
compound occurs mainly as glycoside as a result of linkage to sugar or acetylated sugar
molecules (Stephane et al. 2011). In nature plant phenolics can be in form of flavonoid,
phenolic acid, polyphenolic amides etc. depending on the aglycones structure (Ghaffari,
2012). It passes through the stomach and small intestine as a beta-glycosides unaltered to the
colon where they exert their functions (Ganiyu, 2008). The mechanism of action is linked to
the hydroxyl side chain present in the ring structure (Ghaffari et al. 2014). Phenolic
antioxidants potentials for scavenging free radical are inversely proportional to the number,
position and nature of substation of hydroxyl group in the phenolic compound aromatic rings
(Pham et al. 2018). Consequently, the antioxidant activity of these compounds is attributed to
their redox potentials as they act as reducing agents, metal chelator, hydrogen donors,
quencher of lipid peroxidation, and scavengers of free radicals. They also act to prevent DNA
damage from oxidation, reactive oxygen species, and protect the living organisms’ deleterious
effects of free radicals (Oscar et al. 2020).

2.2. Flavonoids

Flavonoids is a secondary metabolite naturally rich in antimicrobial activities, although this is

more on those lacking hydroxyl group on their β-rings (Senthilkumar and Vijayakumari,
2016). It occurs in nature as a C6-C3 compound linked to an aromatic ring (Sato et al. 1996).
They are also good hepatoprotective, anti-analgesic and anti-inflammatory agent containing
hesperidin, apigenin, rutin, a luteolin, naringenin, apigenin and quercetin (Asha et al. 2015).
Flavonoids occurs as O-glycosides and C-glycosides with flavanone, flavones, flavonol,
isoflavone and chalcone anthocyanidins as derivatives. Its anticancer activity is shown
through activation of cell apoptosis, mechanism of cell cycle arrest, inhibition of proteasome
and carcinogenic enzymes (Oteiza et al. 2005; Fatemeh et al. 2012). High quantity of
flavonoid can be gotten from grapefruit, cocoa beans, thyme, chicory, parsley, cress green tea
etc. (Amiot et al. 2021).

2.3. Alkaloids

Alkaloids are example of secondary plant metabolites derived from amino acids containing
nitrogen in a heterocyclic form (Poonkodi et al. 2017). Example of these hetrocylic alkaloids

4 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

are indoles, isoquinolines, pyroles, pyridines, piperidines, and pyridines (Dhananjay and
Gupta, 2020).

2.4. Terpenoids

This group form the largest and the most diverse group of secondary metabolites and consist
of compounds that are highly enriched in isoprene structure with a general formula of C10H16.
Terpenoids occurs naturally as hemiterpenes (C5), sesquiterpenes (C15), diterpenes (C20),
triterpenes (C30) and tetraterpenes (C40) (Acamovic and Brooker, 2005). They have
antibacterial, antiviral, antifungal and antiprotozoal activities (Yin et al. 2018; Dhananjay and
Gupta, 2020).

3. Phenol-Based Products

Phenols are one of the most abundant heterogeneous compounds in plants with diverse
composition and structure (Delgado et al. 2019; Kumar and Goel, 2019). They have found
many applications of the compounds overtime. Several industrial products incorporate diverse
of types of phenolic (flavonoids, p-D-salicin, tannins, salicylic acid, phenolic acids, lignans,
stilbenes etc.) compounds as part of the major ingredients. They are often used as starter
molecules in the synthesis of intermediate/precursor molecules/compounds including;
Bisphenol A, Xylenols, Caprolactam, Alkylphenols, Aniline, Phenolic resin etc. (Saputera et
al. 2021; Michałowicz and Duda, 2007) and the production of many finished products,
including serving as core structure of many drugs, household products such as disinfectants
(2-Phenoxyethanol and butylatedhydroxytoluene), preservatives, biocides/pesticides (2, 4-
dichlorophenoxyacetic acid, pentachlorophenol, 4-chloro, 2-methyl phenoxyacetic acid, and
diarylether), dyes, mouth wash, tooth paste, explosives, nose drops, cosmetics and textile
production etc., plant derived products (green tea) and processed food items (wine, beer,
chocolate, and coffee) (Del-Rio et al. 2013; Bhuyan and Basu, 2017; Michałowicz and Duda,
2007).

Table 1. The classification of phenol-based products

S/N Class Sub-class Products

1 Precursor compounds Bisphenol A, Xylenols, Caprolactam, Alkylphenols, Aniline,
Phenolic resin
2 Finished products Drugs Sore throat spray, Oral analgesics
Household products Disinfectants, Preservatives, Pesticides, Dyes, Mouth wash,
Tooth paste, Explosives, Nose drops, Cosmetics Soap, and
Textile production
Plant derived products Green tea
Processed food items Wine, Beer, Chocolate, Coffee

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 5

4. Therapeutic Value and Potentials of Phenol

Phenolic compounds are responsible for most of the therapeutic properties observed in herbal
plants (Ahmed et al. 2019). Many phenolic biomolecules including, stilbenes, tannins,
flavonoids, and phenolic acids have been reported to have therapeutic and potential bioactive
abilities (Ozcan et al. 2014; Kalogianni et al. 2020). Some of the most reported therapeutic
effects include; antimicrobial, antioxidant, anticancer, anti-inflammatory, antidiabetic, and
neuroprotective effects (Kumar and Goel, 2019; Saibabu et al. 2015; Ha et al. 2020; Vu et al.
2018).

Figure 1. Therapeutic effects of phenolic compounds.

4.1. Antimicrobial

Phenols have natural defence against many pathogenic organisms (Ozcan et al. 2014).
Generally, with its appreciable penetrating power, it is reported to have bacteriostatic and
bactericidal effects at 0.1–1% and 1 –2% concentrations respectively by using their hydroxyl
groups binding of the active sites to denature and coagulate cell enzymes/proteins (Wickstrom
2016; Cosme et al. 2020). Different phenolic compounds possess antimicrobial activities and
have been reported to inhibit the growth of various microorganisms including fungi, bacteria
and viruses (Ozcan et al. 2014). According to Saibabu et al. (2015); Kumar and Goel (2019)
phenolic acids (e.g., hydroxybenzoic and hydroxycinnamic acids) have inhibitory actions
against common food spoilage bacteria and are used as food preservatives. However, the
antimicrobial effects are inversely proportional to change in pH (Kumar and Goel, 2019).
Also, flavonoids and their derivatives are reported to have antibacterial effect (Naseer et al.
2018). Furthermore, phenolic compounds are also reported to possess synergistic effects in

6 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

combination with antibiotics geared towards combating antibiotic resistant strains (Cosme et
al. 2020).

4.2. Antioxidant Effects

Antioxidants act by limiting oxidation reactions. They scavenge O2 free radicals that could
damage lipids of cell membranes, bind proteins or disrupt nucleic acids structural integrity
(Starowicz et al. 2020; Ha et al. 2020). Phenols are proven antioxidants, having direct and
indirect antioxidant properties (Starowicz et al. 2020; Kumar and Goel, 2019) and the
capacity is related to the number and position of free OH groups (Ha et al. 2020). The more
the free hydroxyl groups, the higher their radical scavenging capacity. In general, phenols
hinder formation of superoxide anion and inhibit key enzymes such as xanthine oxidase,
lipoxygenase, protein kinase, cyclooxygenase, NADH oxidase, S-transferase, and glutathione,
thus halting the production of reactive oxygen species (Ha et al. 2020). Specifically, the
antioxidant activity found in phenolic acids is characteristic of phenol moiety reactivity and
the hydroxyl substituent on the aromatic ring (Kumar and Goel 2019). Several surveys as
reported by (Starowicz et al. 2020) show that majority reported protective effects phenolic
compounds against coronary heart disease risk of diets enriched with polyphenols. In
addition, flavonoids have low redox potential with the ability to donate hydrogen atoms and
electrons, and chlorogenic and caffeic acids are proven antioxidants (Starowicz et al. 2020;
Ozcan et al. 2014). More so, phenolic compounds are able to quench chelation of metal ion
chelation and singlet O2 and they also act as substrates for free radicals such as superoxide
and hydroxyl (Tusevski et al. 2014; Ha et al. 2020).

4.3. Anticancer

Cancer is one of the major health challenges and a leading cause of death in the world today
with death rates two times greater than death rates cause by malaria, AIDS, and tuberculosis
(Kumar and Goel, 2019). As cancer research is going on, the use of compounds originating of
plants including phenols in the treatment of the disease is and will remain a therapeutic
option. Again phenolic compounds/derivatives act at different points, aiding in the prevention
and treatment of cancer via limitation of tumour initiation (Kumar and Goel, 2019). Phenolic
acids, hydrolysable tannins, and flavonoids protect the DNA against damage by free radicals,
by activating xenobiotics detoxification enzymes, inhibiting enzymes processes that cause
pro-carcinogen activation, and by inactivating carcinogens (Vu et al. 2018; Ozcan et al.
2014). The anti-cancer effects of tannins is characteristic to its anti-oxidative properties that
protective the body from cellular oxidation (Ozcan et al. 2014). Thus the high phenolic
contents of guava that produces anti-ageing effects yields curative effects on cancerous cells
(Naseer et al. 2018).

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 7

4.4. Anti-inflammatory

The use of herbal remedies often have low side effects compared to the conventional
medicine (Ahmed et al. 2019) and the use of proven effectiveness of phenolic contents of
plants as anti-inflammatory agents is constantly in the increase (Ahmed et al. 2019).
Inflammation involves the cell and tissue response to damages including the physical,
chemical, biological, and autoimmune damages with symptoms ranging from pain, swelling,
ranging to redness (Mahdi et al. 2013). It is a complex process that involves many immune
cells. Flavonoids such as quercetin (Salehi et al. 2020) has been reported to produce anti-
inflammatory effects which can cause a reduction in the in chronic disease development. This
occurs by the inhibition of enzymes and transcription factors that cause inflammations
(Starowicz et al. 2020). Ahmed et al. (2019) reported the anti-inflammatory effect of
Syzygium cumini leaf extract on rabbit paw. He attributed the anti-inflammatory activities to
flavonoids which are largely present in Syzygium cumini leaves. Again (Naseer et al. 2018)
reported that guava fruit with abundant phenolic compounds can be used as an anti-
inflammatory agent due to its ability to stop infection, thymus production, alteration of heme
oxygenase-1 protein, inhibition of lipopolysaccharide from synthesizing nitric oxide, and its
suppression of the expression of E2. Many phenolic (such as Aspirin) are often used for pain
relief because of their ability to modulate the transcription of the inflammatory mediators or
inhibit (via COX-2 inhibitors) the synthesis and the release of inflammatory lipid
prostaglandin E2 (Mahdi et al. 2013).

4.5. Antidiabetic

Diabetes is an alteration in the metabolic process that occurs as a result of defects in insulin
secretion and functions, and is characterized by chronic hyperglycaemia with irregularities in
the metabolism of carbohydrate, fat and protein (Kamtekar et al. 2014). Phenolics have found
application in the reversal of changes in physiological imbalance/changes due to alteration in
glucose metabolism (Saibabu et al. 2015; Kamtekar, Keer, and Patil 2014). The antidiabetic
effects of phenols such as gallic acid, chlorogenic acid, p-coumaric and protocatechuic acid
occurs through this process of reversing changes in physiological imbalance that alter glucose
metabolism (Saibabu et al. 2015). They improve glucose uptake by enhancing the expression
or translocation of glucose transporter 4 (GLUT4) and PPAR-! and PPARg transcripts, the
activation of AMPK, lowering of glucose and fatty acid production by inhibiting expression
of hepatic glucose-6-phosphatase, enhancing fatty acid "-oxidation, and decreasing oleic
acid-induced triglyceride accumulation.

4.6. Neuroprotective Effects

Neurodegenerative diseases is an increasing problem in the world today, especially for the
elderlies (Li et al. 2016). Risk factors among others include mitochondrial dysfunction and
oxidative damage. Thus, the antioxidant properties of phenolic compounds are valuable in the
protection against neurodegenerative disorders (Li et al. 2016). Specifically, derivatives of

8 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

flavonoids and catechins from studies have demonstrated actions against progressive
degenerative and brain aging conditions such as Alzheimer's and Parkinson's disease (Ozcan
et al. 2014). Also, Resveratrol (trans-3,5,4’-trihydroxystilbene) often associated with grapes
and red wine has demonstrated ability to sustain cognitive process of the brain and
maintenance of healthy nerves (Ozcan et al. 2014).

5. Factors Affecting Phytochemical Properties

The active ingredients of pharmacological interests in herbal drugs can be extracted from
different plant parts using solvent, based on availability or aim of the researcher (Zhi-Xu et al.
2014). Herbal product can be in its crude form or a mixture of certain excipients such as
solvent, preservatives and diluents (Bayliak et al. 2016). Herbal products are usually
marketed as liquid or powdered extract. The choice of plant parts used for herbal preparation
is based on the part that will yield highest activity to the targeted disease condition. To
prepare herbal extracts, the plant parts is first washed with distilled water, and then macerated
to break up cell walls after which particles are percolated or distilled with ethanol, water or a
mixture of ethanol and water to release the phytochemicals into solution. For solid (powered
extracts) the obtained solution is dried to evaporate the solvent (Liu et al. 2018).
Consequently, concentrations of herbal extracts are left in high concentration to increase the
efficacy and pharmacological activities of the herbal drugs. The negative outcome associated
with taking adulterated drugs can be traced to the use of substandard chemicals rather than the
presences of intended or unintended herb in herbal preparation. However, it has been argued
that admixtures (excipients such as solvent, preservatives and diluents) are as result of limited
regulatory policies for instituting centralized tests for authentication of products (Pawar et al.
2017).
Herbal toxicity due to adulteration, wrong dosage intake, and poor-quality of extraction
solvent may manifest in a number of organs such as liver, kidney, nervous system, stomach
and the blood which is the connective tissue of a living system (Galimberti et al. 2013). Since
the liver is the key organ for regulation of metabolic functions and detoxification of
substances such as heavy metals, microbial contaminants and drugs (Phoolcharoen and
Sukrong, 2013), exposing it to these compounds weakens its responses and protective
mechanisms as result of cellular necrosis and increase in serum levels of biochemical
parameters such as alanine aminotransferase (ALT), and aspartate aminotransferase which is
a primary diagnosing tool used in accessing the stability and functionality of a healthy system
(Raclariu et al. 2018).
Herbal products have various sources (geographical location) and therefore may contain
heavy metals or microbes during the course of harvesting and processing (Pingale et al.
2011). A high level of sanitation and hygiene are maintained in order to reduce and avoid
alterations and contaminations during herbal medicine production. Currently safety, quality
and efficacy are the issue of concern for herbal products due to increase in demand and
commercialization of herbal products across the globe (Newmaster et al. 2013).
Other challenges that affect the production of herbal products include poor identification.
Most plants used for production of herbal drugs are collected by local people who have little
or zero scientific knowledge of the plants but are dependent on their experiences and

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 9

recommendations from other herbalists and traditional medical practitioners (Urumarudappa

et al. 2016). As a result, related plant species with similar morphology features may be
collected while picking plants for herbal medicine production leading to adulterated herbal
drug. This is often linked to confusions with the local names of the plant species, poor record
of, morphological similarities between the plant species (Speranskaya et al. 2018). Scientific
methods such as microscopic and macroscopic studies, organoleptic and chemical analyses
have been developed for tracing adulteration in herbal drugs (Kreuzer et al. 2019). Regulatory
bodies should engage the use of DNA technology to investigate substandard products (Heigl,
2003).
Herbal producers should subject their herbal process to techniques such as DNA
barcoding which is a low-cost and effective tool used for automatization and rapid
identification and traceability of plant species (Poetsch et al. 2006). Poor identification of
plant species and use of sub-standard chemicals used in herbal medicines, as either single
herbs or poly-herbal products lead to lack of uniformity in their chemical composition and
physical qualities of herbal medicines. These factors have contributed to the herbal medicine
being reported as inferior with questionable quality and authenticity in the scientific and lay
media (Thakur et al. 2011).
Major factors that affect the stability and quality of herbal products include temperature,
pH and moisture. For every 10°C rise in temperature, there is two to three times increase in
chemical reactions in herbal drugs. Additionally, alkaline pH decreases the antioxidant
activity of plant extracts and increases their pre oxidant activities. The protective capacity of
plant extracts against oxidative and other stresses decreases with low alkalinity. On the
other hand, moisture increase the decomposition rate of herbal drugs especially for those
herbs that are susceptible to hydrolysis (Tripathi, 2006). In addition, enzyme presence
increases chemical degradation in herbal products. Hence, unfavorable temperature or pH
may denature the enzyme resulting to loss of activity. The active constituents in herbal
formulations include as alkaloids, tannins, glycosides, flavonoids etc. Therefore poor reacting
condition may after the stability of each component of the herbal mixture (Rivera et al. 2013).
Other factors that affect the stability of herbal drugs include humidity, light and air, oxygen,
carbon dioxide and water vapours, (Wienkers and Heath, 2005). More so, pH, particle size,
presence of chemicals, nature of container, and the properties of water or other solvents used
in the herbal drug production influence the stability of the product (Shi et al. 2019).

6. Antioxidant Properties of Phenols

Phenolic compounds are naturally occurring antioxidants present in plant foods. They are
called primary antioxidants and are mainly free radical scavengers (FRS). They are capable of
delaying or inhibiting the commencement step or interrupting the proliferation step in lipid
oxidation thereby lowering the production of unstable breakdown compounds such as
aldehydes and ketones which cause rancidity (Shahidi and Ambigaipalan, 2015). The
antioxidant properties of the phenols are as a result of the existence of the -OH group bonded
to the benzene ring of these aromatic compounds. Polyhydroxy phenolic compounds possess
more than two -OH groups linked to the aromatic ring whereas polyphenolic compounds
contains more than one phenol moiety (Zeb, 2020).

10 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

Phenolic antioxidants have been studied to a great extent in some foods materials
obtained from plants such as vegetables, berries, onion bulbs, tea, fruits, cereals, seeds, wine,
and vegetable oils (Boskou, 2006). Phenolic compounds can scavenge free radicals that are
present in the body and convert them into less reactive forms, thereby hindering free radical
progressions that could result in many health challenges (Min et al. 2021). Santos-Sánchez
(2019) reported that phenolic compounds can easily give out H+ from the –OH group attached
to the ring or chelate metal ions including iron and copper ions. The overall effect leads to the
stoppage of the oxidation of low-density lipoproteins (LDL). Similarly, Amarowicz (2016)
described the inhibition of LDL oxidation by some naturally occurring phenols. Cazzola et al.
(2016) reported that the -OH groups found on the aromatic ring of polyphenols have the
ability to effectively donate active hydrogen and intently neutralize reactive oxygen free
radicals. While naturally occurring phenolic compounds are safe and very effective at
combating free radicals, the synthetic antioxidants have been reported to be toxic and
carcinogenic and their prolonged consumption may be harmful to the human body (Lv et al.
2021).
Giada (2013) observed that the antioxidant activity of phenols relied greatly on their
chemical composition. Out of the phenolic compounds that have known antioxidant activity,
flavonoids, coumarins, chalcones, tannins and phenolic acids are reported. Flavonoids make
up the most powerful antioxidant group found in plants. Their excellent antioxidant property
is linked to the presence of -OH groups on their ring structure. Even though the antioxidant
properties of tannins have not been highly recognised like the actions of flavonoids, new
study show that the level of polymerization of these compounds is connected to their free
radical scavenging abilities. In addition, chalcones and coumarins have antioxidant properties,
however data related to their antioxidant activity are not many (Mazzone et al. 2015).
Phenolic acids as well as their esters have also been shown to possess great antioxidant
properties, with specific examples to include chlorogenic acid, hydroxybenzoic acid, caffeic
acid and hydroxycinnamic acid. Their antioxidant activities are related to amount of hydroxyl
groups present in the compound. Generally, the hydroxylated cinnamic acids have better
antioxidant activity when compared to their corresponding benzoic acids (Giada, 2013).
There are several determinants that control the antioxidant property of phenolic
compounds. Firstly, their capacity to give out a proton depends on the redox potential
between the phenolic compound and targeted free radicals. Shahidi and Ambigaipalan (2015)
confirmed that phenols with lower reduction potential than the free radical would easily give
out its hydrogen moiety to the oxidant except if the reaction is not kinetically feasible. In
addition, the relative placement of certain functional groups on the phenolic ring has a
profound effect on their antioxidant property. Phenolic compounds with the -OH group
attached at the ortho position and/or para position on the phenolic ring have higher
antioxidant activity than Phenolic compounds with –OH attached to the meta position (Göçer
and Gülçin, 2011). There is a higher antioxidant activity when the methyl group attached at
para-position is substituted with an ethyl or an n-butyl functional groups (Shahidi and
Ambigaipalan, 2015). Furthermore, the number of hydroxyl groups present on the aromatic
ring influence its antioxidant potential activity. Flavonoids have been found to have more
antioxidant activity than their phenolic acids because they possess more –OH groups (Zhang
and Tsao, 2016).
Apart from the extent of the -OH groups on the aromatic ring of phenolic compounds and
their relative positions, their antioxidant activity is also exerted by its chemical structure

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 11

principally the aromatic nucleus. The aromatic nucleus is accountable for the stable nature of
the antioxidant compounds after their interacting with free radicals. Phenolic acid such as
gallic acid contains three –OH groups which are responsible for its antioxidant property. It
interacts with free radicals to form gallic acid-free radical and made stable by effect of
resonance from the aromatic nuclei (Phonsatta et al. 2017; Rajan and Muraleedharan, 2017).
Furthermore, the bond dissociation energy (BDE) of the hydrogen atom in the hydroxyl
group attached to the phenol is also another consideration in examining the antioxidant
function of phenolic compounds (Leopoldini et al. 2011). A lower BDE value shows the
easiness with which the -OH bond dissociates and its subsequent interaction with a free-
radical specie (Chen et al. 2020). Apart from BDE, ionization potentials (IP) showed a
different pattern of reaction for phenols and their respective antioxidant property (Leopoldini
et al. 2011).
Antioxidant property of phenols from food sources has numerous health benefits due to
their potential to prevent the onset of many ailments caused by free radicals. In addition,
some of these compounds have pharmacological properties and have been used for
therapeutic purposes. These important characteristics exhibited by phenolic compounds have
been associated to their role in reducing risks of neurodegeneration, osteoporosis,
cardiovascular diseases, cancers, and menopausal symptoms (Shahidi and Ambigaipalan,
2015). Therefore, the possible mechanism of protection by phenolic compounds, including
flavonoids, was ascribed to their unmediated neutralization of reactive species and metal ions
chelation.

7. Mechanism of Action of Phenolic Antioxidants

The antioxidant effects of phenolic compounds can occur through different processes such as
through HAT, hydrogen atom transfer, mechanism, single-electron transfer (SET) (Zhang and
Tsao, 2016), SPLET, sequential proton loss electron transfer (Lee et al. 2020) or transition
metal chelation (TMC) (Zeb, 2021). These mechanisms show the significance of phenolic
compounds in scavenging free radicals.

Figure 2. Phenolic antioxidant mechanism of action via HAT and SET (Liang and Kitts 2014).

12 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

7.1. Hydrogen Atom Transfer

This mechanism of action allows phenolic antioxidants to scavenge free-radicals by

transferring hydrogen atom from the hydroxyl group to the reactive free radicals (Zeb, 2020).
The free radicals on acquiring a hydrogen atom forms neutral and stable structures, while the
phenolic antioxidant is transformed to an antioxidant free radical (Figure 2). The phenolic
antioxidants have the ability to undergo HAT mechanism to form non-radical species (R:H,
R:OH, or R:OOH) and antioxidant free radicals (B*) as depicted in Figure 3.
The antioxidant free radicals (B*) formed are less reactive because they are stabilised by
several factors. The antioxidant free radicals (B*) can further react with free radical substrates
to from non-radical products. In the hydrogen atom transfer mechanism, bond dissociation
enthalpy determines the antioxidant activity of the phenolic compound. Therefore, reduced
BDE increases the inactivation of free radical propagation in hydrogen transferring group in
potential phenolic antioxidants (Leopoldini et al. 2011).

Figure 3. Reactions of phenolic antioxidants (B:H) and antioxidant free radicals (B*) with and with
free radicals (R*, RO*, or ROO*).

7.2. Single Electron Transfer (SET)

In SET mechanism, the phenolic antioxidant ( B:H) donates a single-electron to a potential

target substrate (A*) to produce an intermediate free radical which can then enter other
metabolic pathways as depicted in Figure 3. In the SET mechanism, there is an electron
transfer from the nucleophilic antioxidant to the substrate containing free radical which
results to the oxidation of the nucleophilic antioxidant to cationic radical. Also, the ionization
potentials (IPs) of the participating atoms of the phenolic antioxidants are one of the
important constraints in the estimation of scavenging activity. The lesser the IP value, the
faster the phenolic antioxidant would easily donate its electron to the free radicals and
subsequent reactions (Apak et al. 2016). This in turn increases the antioxidant activity
property of the phenolic antioxidant. The HAT and SET reactions occur simultaneously and it
is often difficult to differentiate the two mechanisms. However, the mechanism of activity
could be evaluated from the structure of the phenolic antioxidants and solubility properties
(Leopoldini et al. 2011).

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 13

7.3. Sequential Proton Loss Electron Transfer

The first process in this mechanism involves the phenolic antioxidant donating its proton to
become an anion. Simultaneously, it transfers an electron to the free radicals leading to the
formation of neutral and stable compound (Figure 4). In SPLET mechanism, the activity of a
phenolic compound in scavenging for free radical is determined by estimation of its proton
ability (PA) and the electron transfer enthalpy (ETE). The PA value represents ease at which
phenolic compounds donates a proton while the ETE value determines the potentials of the
resulting phenolic anions to give electrons to the oxidants. Certain groups at various positions
on the aromatic nuclei of phenolic compounds have been found to affect the PA values. For
instance, electron-donor groups such as the OCH3 group attached to ortho position of
phenolic rings have been reported to show slight elevation of PA values while an electron
withdrawing group such as NO2 slightly reduced it. Conversely, the ETE values was greatly
reduced by the OCH3 group while the NO2 group increased ETE (Lee et al. 2020). Anitha et
al. (2020) studied the activity and the antioxidant properties of catechin and epicatechin by
applying the density functional theory and discovered that the –OH group at 4-site on the B-
ring, appeared to be involved in proton donation. In addition, the polar solvents favoured the
SPLET mechanism. In the same way, polar conditions also favoured SPLET mechanism for
diterpenoids and coumarins (Vo et al. 2020; Wang et al. 2020).

Figure 4. Proposed mechanism of phenolic antioxidants via SPLET. (A) Proton ability (PA), (B) and
electron transfer enthalpy (ETE) (Zeb 2020).

7.4. Transition Metal Chelation

Phenolic compounds also play antioxidant roles via transition metal chelation (TMC).
According to Brown et al. (1998) phenolic compounds enable the stabilization of transition
metals through chelation. Transition metals such as manganese (Mg), copper (Cu), and cobalt
(Co) are able to form coordinate bonds when interacted with phenolic antioxidants.
Transitions metals bind tightly to proteins and are often very harmful their free forms. Thus
TMC mechanism exerted by phenolic compounds is very important to control the level
transition metal ions especially under certain conditions that would release these reactive
metals from proteins (Chen et al. 2016; Baruah et al. 2018). Phenolic compounds from foods
are excellent at metal chelation and usually form complex with these metals.

14 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

Phenolic compounds possess high antioxidant potential. However, their ability to chelate
with transition metals and reduction potentials could be different as a result of their
differences in structure. For instance, the ability of cucumin to chelate metal ions like copper
and iron is attributed to the keto-enol moiety in their structure which is essential in
Alzheimer’s disease pathology (Bu et al. 2016; Mary et al. 2018). The high ability of
flavonoids to sequester transition metals and neutralise free radical species is a characteristic
of the catechol moiety on ring B, 2,3-double bond and conjugated 4-oxo group on C- ring and
3 and 5-hydroxyl groups (Belščak-Cvitanović et al. 2018).

8. Safety and Efficacy of Phenol-Based Products

Phenolic compounds are a class of small molecules with at least one phenol unit in their
structure. According to Gan et al. (2018) phenolic chemicals are separated into subgroups
such as tannins, quinones, phenolic acids, lignans, coumarins, stilbens, flavonoids, and
curcuminoids on the basis of chemical structures. These phenol-based products are
unconventional or traditional medical treatments that contain the phenolic chemicals listed
above. Unconventional or traditional medical treatments are widely used around the world
(Zamawe et al. 2018). Complementary and alternative medicine (CAMs) is the umbrella term
for these non-biomedical treatments (NBTs). WHO recognizes the importance of high-
quality, safe, and effective complementary and alternative medicine (CAM) in ensuring
universal healthcare access? As a result, the WHO traditional medicine strategy for 2014 to
2023 is focused on maximizing the potential contribution of complementary and alternative
medicine (CAM) in healthcare safe and effective use of it but there is dearth of knowledge on
the utilization of this safe and alternative form of medicine. Hence, there is need to conduct
more research and find rigorous evidence in this field. Herbal medicine is a major and popular
form of complementary and alternative medicine (CAM) therapy and involves the use of
whole plants, plant extracts and plant derived chemicals in the treatment of diseases. This is a
survey to determine the most commonly used phenol-based herbs around the world, as well as
to assess their efficacy and safety.
Echinacea is most commonly used to treat colds. Nine of the 16 randomized, placebo-
controlled Echinacea trials examined in a recent study were positive, while the other seven
were negative. There is some evidence of potential efficacy of Echinacea purpurea potential
efficacy in the treatment of the common cold but the results are inconsistent. There is
evidence that Echinacea reduces the incidence of infections in the upper respiratory tract.
However there are controversies surrounding its clinical significance and application in
Medicine. There was no evidence of a difference in the length of time that upper respiratory
infections lasted. In terms of echinacea's safety, there appears to be none, at least in the short
run. The risk of selective reporting and methodological variation limits the robustness of these
conclusions (David and Cunningham, 2019). In large, high-quality subsequent randomized
controlled trial, Echinacea angustifolia was discovered to be ineffective in treating
experimentally created rhinovirus infections. According to some experts, finding an influence
would have been more plausible if a higher dose or a different species of Echinacea purpurea
was utilized. Preliminary studies show that Echinacea may have anxiolytic properties.
Echinacea angustifolia extract has successfully been used to lower the anxiety level of mice

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 15

exposed to elevated plus-maze, shock-induced social avoidance tests and social interactions.
Consequently, a randomized controlled test with 108 individuals having mild to moderately
severe anxiety was carried out to investigate the effects of 20 mg of placebo and 40mg of
Echinacea angustifolia respectively. Individuals were given 20 mg of placebo or 40mg of
Echinacea angustifolia two times in a day for a period of six weeks in a three-arm parallel
group. From the results, adults with mild-to-moderately severe anxiety treated with
Echinacea angustifolia extract (EP107TM) show lesser improvements than adults who were
given 40 and 80 mg of placebo daily for a period of 6 weeks. However there was a significant
improvement in the emotional wellbeing of the individuals indicating antidepressant
properties in Echinacea angustifolia extract (Lopresti and Smith, 2021). Previous studies
found that Echinacea and placebo groups had the same rate of side effects (Lopresti and
Smith, 2021). Although, data points did not reveal any safety concerns with Echinacea used
in a large population over an extended period of time, the possibility of it causing uncommon
and rare adverse effects cannot be ruled out (Jawad et al. 2012).
For thousands of years, Panax Ginseng has used as herbal plant in traditional medicine in
Asian continent. However, there was no comprehensive assessment on the quality and
quantity of ginseng clinical research. More recently, interest has been shifted into ginseng
clinical trials (GCTs) investigating the safety and the efficacy of using in the herb in
traditional medicine.
A recent study conducted by Fan et al. (2020) which employed a summary of 119
published ginseng clinical trials (P-GCTs), and 152 registered ginseng clinical trials (R-
GCTs) with inclusion of other features such as source registry, primary purpose of trial,
recruitment status, length and sample size, conditions and outcomes shows that the average
period of ginseng treatment is less than 3 months. Ginseng, ginsenosides and prescriptions
containing ginseng were administered to patients suffering from cardiovascular diseases and
metabolic ailments to examine the preventive and healing properties of ginseng. After a
thorough examination of each study, 22 of 95 panex Ginseng clinical trials (P-GCTs) with a
duration of less than three months yield negative results, while two of twelve P-GCTs with a
duration of three to six months yield invalid data (Chen et al. 2020; Jung et al. 2020). All 12
trials above 6 months intervention period showed substantial results. The implication shows
that ginseng's efficacy can be improved through long-term intervention. Current research
works shows that ginseng is well tolerated and safe to be used for more than 6 months after
oral ingestion. About 79.8% of published articles on ginseng use in medicine indicate that
Ginseng hold great potentials and good impact for use as herbal medicine. Studies conducted
in vitro and in vivo with human clinical trials have indicated that ginseng extracts used in
disease treatments yield no negative effects on humans (Ramanathan and Penzak, 2017). A
recent randomized clinical trial conducted with 1000 individuals divided into two groups with
a placebo treatment group and KRG supplement treatment group (which were administered
with 2 g/d of KRG supplements) showed that KRG is safe and tolerable in humans (Song et
al. 2018). Ginseng supplementation has been clinically associated with adverse cardiovascular
events. According to records in literature, misuse and extended use of ginseng result to side
effects relating to cardiovascular events such as atrial fibrillation, elevated blood pressure and
long QT syndrom (Paik and Lee, 2015). Although several clinical research have proved the
efficiency and safety using of Ginseng herbal medication, there is still need to conduct more
controlled randomized large-scale research trials.

16 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

Ginkgo biloba (G. biloba) is a herbal preparation that contains terpene lactones, such as
Bilobalide and Ginkgolides A, B, and C, and flavone glycosides (Ginkgolides A, B, and C),
isorhamnetin, quercetin, and kaempferol (Li et al. 2021). The herb also has the ability to
lower blood sugar and blood pressure, combat hypertension, triglyceride and lipoprotein
abnormalities. Furthermore, it is utilized in the treatment of metabolic syndrome (MetS)
which is a major cause of cardiovascular diseases. G. biloba and Ginkgo biloba extract (GBE)
have shown beneficial effects on various aspects of the metabolic syndrome (MetS),
including cardiovascular disease, hypertension, obesity, dyslipidemia, and Type 2 diabetes
mellitus (T2DM). Low density lipoprotein (LDL) and triglyceride (TG) levels are reduced by
G. biloba, whereas high density lipoprotein (HDL) levels increase. Endothelial nitric oxide
synthase (ENOS) expression is increased by the GBE to lower blood pressure (BP). By
boosting glucose consumption and insulin sensitivity, it lowers blood glucose levels (Eisvand,
Razavi, and Hosseinzadeh 2020). Alzheimer's patients may benefit from ginkgo biloba (AD).
Ginkgo biloba L. leaf extract (EGb) has been used studies investigating the treatment of
Alzheimer's disease (AD) since the 1980s, and many other clinical investigations were
conducted through the subsequent 30 years. Though EGb's role in the treatment of
Alzheimer's disease (AD) is still up in the air, recent studies have shown promising results.
Since the 1980s, clinical trial papers published on the effects of EGb on cognitive function
have been compiled from databases that include Elsevier, Pubmed, Europe PMC, etc. (Liu et
al. 2020). Patients with mild dementia may benefit from taking EGb for a longer period of
time (at least 24 weeks) and at a higher dosage if the results of studies and comparisons
studies supports this hypothesis (240 mg per day). GBE may induce mild to moderate side
effects such as headaches, dizziness, mild gastrointestinal distress, constipation, and allergic
skin responses when recommended dosages are ingested orally.
On the other hand, higher doses of GBE may lead to restlessness, nausea, vomiting,
diarrhea and general body weakness (Shaito et al. 2020). Indication from published case
reports show a temporal relationship between GBE ingestion and systemic side effects such
as bleeding, and intracranial bleeding (Bent, 2008). These effects are as a result of the
antagonism against platelet-activating factor exerted by ginkgolides, bilobalides, and other
constituents of G. biloba extracts (Izzo and Ernst, 2009). A double-blind, placebo-controlled,
randomized pilot conducted by Lim (2012) showed G. biloba extracts are more likely to cause
ischemic stroke and transient ischemic attack more than placebo supplementation. From the
trial, individuals were treated with G. biloba extracts and placebo for 42 months. About 118
cognitively stable participants were assigned to standardized GBE or a placebo group to
examine the effect of G. biloba extracts on degeneration of cognitive abilities (Lim, 2012).
Other in vivo studies in rats have been used to examine the safety of Ginkgo biloba in herbal
medicine. Aged rats with spontaneous hypertension (SH) feed with GBE (0.5 percent extract)
for a period of 4 weeks showed a dramatic lower heart rates and lower blood flow velocities
than rats used in the control group (Heinonen and Gaus, 2015). Consequentially, there is need
to evaluate the impact of GBE usage in aged people with hypertension (Chen et al. 2019). The
safety of GBE and its long-term use in human subjects is still under debate. For that reason,
there is need for subsequent investigations and extensive clinical trials designed for use in
human subjects.
Ganoderma lucidum known commonly as "lingzhi" or "reishi," is an herb used in the
production of different forms of herbal medicine. Mycelia and fruit body of the plant are
utilized in making commercial forms of G. Lucidum. Chan et al. (2021) evaluated the

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 17

effectiveness of Ganoderma lucidum in treating cardiovascular diseases (CVD) using a

double-blind placebo-controlled study. In the study, 84 individuals suffering from type 2
diabetes mellitus and metabolic syndrome were administered with either G. lucidum, G.
lucidum supplemented with Cordyceps sinensis or placebo to evaluate the efficacy of G.
lucidum in the treatment of cardiovascular diseases and hyperglycaemia. Evidence from the
study showed no support in the use of G. lucidum for treating either cardiovascular diseases
or hyperglycaemia and metabolic syndrome. Consequently, Shaito et al. (2020) reported that
the herb is ineffective in lowering blood pressure but is effective in the treatment of
hypertension when used in conjunction with traditional cardiovascular disease treatments.
Other studies have revealed that G. Lucidum use in medicine is completely safe. G. lucidum
extracts function indirectly on DNA increasing the safety of the compound against
doxorubicin which is used in chemotherapy as a DNA intercalating agent used in
chemotherapy (Gurovic et al. 2018). In another study, G. lucidum was administered in 1.44
g/day to 23 dyslipidemic and moderately hypertensive individuals for a period of 12 weeks to
determine the safety of using the herb in traditional medicine. G. lucidum produced no
negative effect when compared to a placebo treatment used as the control. However,
symptoms which were not considered clinically significant such as influenza, runny nose and
headaches were observed (Shaito et al. 2020). Polysaccharides obtained from G. lucidum
were tested for safety using Wistar rats and the indications from the study showed no aberrant
clinical indications, mortality, or substantial changes in body weight and food intake
behaviours of the rats. Consequently, there were no observable changes in the clinical
chemistry, hematological values, and in the organ/body weight of the rats. In another study
conducted by Duan et al. (2021) Kunming mice showed no evidence of mutagenicity when
treated with lower doses Polysaccharides. However, Shaito et al. (2020) reported that high
doses of G. lucidum polysaccharides altered immune responses in the mice and increased
immune response to the sheep red blood cells even though there was no recorded influence on
phagocytic or macrophage function.
Ginger (Zingiber officinale Rosc.), is a plant popularly known across the globe as an
aromatic spice and herb used medicinally to treat a large number of ailments such as arthritis,
rheumatoid arthritis, and variety of other conditions (Ansari et al. 2021). Yamprasert et al.
(2020) conducted a controlled randomized study to compare the effects of ginger extracts and
Loratadine on the treatment of Allergic rhinitis. Patients were divided into two groups which
were given 500 mg (n = 40) of ginger extract and loratadine 10 mg (n = 40) respectively for
3- and 6-week period. The efficacy of the treatments was evaluated using clinical
examinations that include total nasal symptom scores (TNSS), rhinoconjunctivitis quality of
life questionnaire (RQLQ) and the cross-sectional area of nasal cavity using acoustic
rhinometry (ARM). The safety of the treatment methods was measured by blood analysis,
blood pressure, and history-taking for side effects. TNSS in patients were assessed using four
aspects: itchy nose, nasal congestion, runny nose and sneezing with scores of ranging from 0
as no symptoms to 12 as maximum symptom intensity. RQLQ used in the study comprised of
28 questions in 7 categories (sleep problems, practical problems, nose symptoms, eye
symptoms, activity limits, non-nose/eye symptoms, and emotional function). In the activity
domain, there are three patient-specific items that allow patients to select three activities in
which their rhino conjunctivitis is the most limiting factor. Patients answered questions on a
seven-point scale, with 0 denoting no impairment and 6 denoting significant impairment. The
ARM diagnostic tool was used to evaluate nasal patency and estimate nasal cavity and the

18 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

nostril distance. After the period of treatment, groups treated with ginger showed a lower
TNSS scores than groups treated with loratadine showing less severity of symptoms in
patients. Ginger extract treatment yielded 0.094 cm3 (p 0.02) increase in left nasal volume as
well as a 0.02 cm (p 0.01) decrease in left nose distance. The loratadine-treated group, on the
other hand, did not improve significantly. Although there were no significant difference for
the RQLQ in both groups, patients treated with ginger showed a reduction in RQLQ score by
0.283 points against loratadine group (Yamprasert et al. 2020).
For AR patients, ginger extract works just as well as loratadine in reducing nasal
symptoms and improving overall well-being. Ginger effects on human milk volume were also
examined in randomized controlled trials (RCTs). In this study, 24-hour human milk volume
was the primary endpoint. There were five RCTs in our database. In two studies, ginger was a
solo intervention (Sassanarakkit et al. 2019), while in three investigations, ginger was
combined with other herbs (Bumrungpert et al. 2018). Ginger has been found to increase the
volume of human milk in mothers who gave birth vaginally. It didn't help mothers who had
caesarean sections increase their milk supply (C-section). Some combination items, such as
ginger with pandan, turmeric with fenugreek, and Xionggui-tiao-xue yin, have been
demonstrated to increase human milk volume. Ginger was found to have no negative impact
on the study's results. Human milk volume can be increased with ginger in vaginal birth
mothers but not in C-section mothers. It is also possible to increase the volume of human milk
by combining ginger items (Dilokthornsakul et al. 2021). In the two studies that were
included, ginger was used exclusively without any side effects to improve human milk
production (Paritakul et al. 2016). According to Bumrungpert et al. (2018), using ginger in
combination with turmeric, and fenugreek yields mild side effects that include as headaches
and rashes as well as nausea and excessive rectal gas as well as fatigue and bloating as well as
abdominal pain and urine that smelled like maple syrup (Bumrungpert et al. 2018).
Nonetheless, there was no observable difference between women who received the
intervention and those who received a placebo. It has also been found that some of the
unpleasant effects associated with turmeric, such as gastrointestinal adverse effects that
include diarrhoea, yellow faeces, nausea, and cutaneous adverse effects such as rash, may be
exacerbated by the combination of turmeric and ginger (Hewlings, 2017). According to a
previous review (Dilokthornsakul et al. 2021), ginger is regarded as a safe herbal medicine,
and no other adverse events have been observed when ginger is used alone in a clinical
setting. Therefore, there is no conclusive proof to show implication of using ginger to
improve lactation in humans.
Garlic is a popular aromatic spice and herb used medicinally for a wide range of curative
applications due to its excellent health-promoting and disease-preventative effects (Chan et al.
2020). Clinical studies have revealed that the risk of developing human diseases such as
cardiovascular and metabolic disorders, diabetes, blood pressure, and cancer can be reduced
by garlic and its secondary metabolites. Specific characteristics such as anti-inflammatory
properties, antioxidant properties and the ability to lower lipids percentage enables this
therapeutic applications if garlic in medicine (Ansary et al. 2020). Garlic has been shown to
be an effective treatment for hypertension and dyslipidemia in double-blind randomized trials.
Indications from the findings of this review shows that s-allyl cysteine or garlic power from
the range of 600–2400 mg can be utilized as an adjuvant therapy to standard treatment in
hypertensive patients with SBP above 140 mmHg. Consequently, it is beneficial to administer
300–600 mg of coated garlic powder on a daily basis to individuals with TC > 6.0 mmol/L

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 19

and LDL-C > 3.0 mmol/L (Chan et al. 2020). Due to a lack of information and poor study
designs, there is a lack of data supporting various garlic formulations and dosages. Hence
there is a dearth in knowledge to the use of garlic in the treatment of dyslipidaemia. Aged
garlic extracts administered in 1.2–2.4 mg s-allyl cysteine/day have been revealed to have
hypotensive effect as well as coated garlic powder tablets given in 600–2400 mg/day. To
prepare aged garlic, cloves are soaked in solution for about 20 months to allow the enzymatic
synthesis of sallyl cysteine from sallyl cysteines derived from glutamyl-sallyl-L-cysteine
(Pathak et al. 2020). Garlic, on the other hand, appears to have little data supporting its
potential usefulness in the therapy of dyslipidemia at this time. There have been a few reports
of minor side effects, but nothing serious (Chan et al. 2020).
It has been proven that Lian huaqingwen (LH) is effective against influenza (K. Chen and
Chen 2020). LH has been reported to show promontory effect in the treatment of patients
suffering from COVID-19. Lian huaqingwen (LH) efficacy and safety in treating COVID-19
patients was assessed using the randomized controlled trials. Two RCTs reports compared the
recovery rate and overall effectiveness of LH with conventional treatment methods. The
findings show that clinical symptoms such as fever, weariness, and muscle discomfort to be
major experiences in COVID-19 patients treated with Lian huaqingwen (LH). More so, LH
has been used in combination with other medications to treat people with COVID-19.
However, there is no evidence showing the safety and efficacy of this treatment method (Liu
et al. 2021).

9. The Way Forward: The Use of Novel Drug Delivery Systems

Antioxidants are considered supplements which are effective in modulating redox process and
various pathological diseases. An increased oxidation and associated systemic inflammation
are frequently seen in degenerative diseases and autoimmune disorders, such as those
observed in rheumatoid arthritis, Alzheimer’s disease etc. Antioxidants modulate the cellular
redox processes experienced in such ailments. Examples of these antioxidants include natural
polyphenols such as phenolic acids resveratrol, flavonoids and curcumin. However, there are
challenges associated with the use of therapeutic polyphenols. This challenges include, low
bioavailability and instability in water (Guernelli et al. 2020). Properties such as presence of
multi rings polyphenols, low lipid solubility, and high molecular weight contribute to the low
bioavailability of phytoconstituents in polyphenols (Barani et al. 2021).
Development of new drug delivery system (NDDS) for herbal drugs is one of the major
focuses of research in herbal medicine in recent times. There are two purposes for the
development of these NDDS. The first role of the NDDS is to release the drugs at a rate that
corresponds to the body needs. The NDDS are also designed to concentrate the active
constituents of herb drugs in the target site or organ. The prolonged release dosage forms of
conventional dosage has failed to meet the needs of drug delivery (Ajazuddin and Saraf,
2010). Therefore the intervention of NDDS brought numerous advantages which include
enhanced solubility and bioavailability, improved side-effects profile, protection from
autoimmune, sustained and prolonged delivery of active principles, physical and chemical
degradation, and enhanced stability in herbal formulations (Chaturvedi et al. 2011).

20 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

As a result of these advantages, nano-sized NDDS have the potentials to boost the
pharmacological activities of herbal formulations as well as overcome the challenges
encountered with their use. These special drug carrier systems are useful in enhancing drug
penetration, and achieving controlled drug release; as well as targeting of various body organs
(Sunkireddy et al. 2013). With the development of nanotechnologies, formulation of nano
polyphenols (polyphenols encapsulated nanoparticles) has been made possible.
Solid-lipid nanoparticles, liposomes, polymer nanoparticles and polymeric conjugates are
some of the nanocarriers that have been developed for the delivery of polyphenols in
treatment of various diseases (Salehi et al. 2020). These carriers are grouped into three
categories viz vascular delivery system (liposomes, transfersomes, phytosomes, Ethosomes),
Nano-sized drug delivery systems (micropallets, microspheres, nanoparticles) and Biphasic
drug delivery systems (micro and nano-emulsions). According to Barani et al. (2021) phyto-
phospholipid complexes (named phytosomes) are more efficient in improving the
bioavailability of polyphenols from all approaches.
Liposomes are colloidal structures which are that consist of lipids, phospholipid bilayers
and an inner aqueous compartment(s). Because of their design, liposomes possess the ability
to increase bioavailability, enhance sustained topical delivery of active principles, and
overcome toxicity and adverse events associated with drug overdose (Hajialyani et al. 2018).
The other advantages of this NDDS is its ability to accommodate both hydrophilic and
hydrophobic entities, in addition to being biodegradable and essentially non-toxic vehicles
(Ajazuddin and Saraf, 2010). Liposomes encapsulating phytoconstituents from herbal extracts
increase the permeation, solubility and therapeutic activity of herbal drugs. They also protect
the drugs against all forms of degradation (Barani et al. 2021). Liposomes are especially used
in many anti-aging products to encapsulate vitamins, antioxidants, and natural botanical
extract (Alğin-Yapar 2017). In research by Ramona et al. (2018), liposomes containing E.
purpurea were formulated using thin-film hydration method. Characterization and evaluation
studies of lipid-loaded vesicles showed that the sizes of the liposomes were smaller than 200
nm, and an encapsulation efficiency of about 80%. The liposomes were stored for 90 days at
4°C, and were observed to have good stability during this period; an outcome that was not
surprising since their polydispersity index was low. The research also revealed that
formulating E. purpurea as a liposomal formulation caused a reduction in burst release,
resulting to a controlled release of the drug (Pavaloiu et al. 2018). A study on encapsulation
of polyphenols from Lycium barbarum suggests that liposomal formulations could be
considered great strategy for the delivery of some antioxidant substances, such as polyphenols
(Păvăloiu et al. 2021).
Transfersomes were designed as an improvement to liposomes, hence their structures are
more deformable or elastic. This became necessary because of the inability of liposomes to
penetrate into deep layers of the skin. Transfersomes are elastic and ultra-flexible when
compared to other lipid carrier systems. They also contain highly deformable membranes
which enhance the delivery of compounds to deeper tissues in the skin and assemble into a
lipid bilayer and close into a lipid vesicle when applied to aqueous systems (Barani et al.
2021). One of the primary advantages of transfersomes is their ability to interact with skin
moisture and retain water. Large amount of hydrophilic molecules present in transfersomes
prevent skin dehydration. Hence, they are used extensively in drug applications that target
passing molecules through the transdermal route (Pradeep and Kumar 2018). Formulations
consisting of self-assembling gellan-transferosome supplemented with baicalin provide

Therapeutic Role of Phenolic Antioxidants in Herbal Medicine 21

excellent deposition of baicalin in intact skin. This formulation is used to produce maximum
polyphenol protective effect on inflamed skin causing a complete repair of skin inflammation
(Manconi et al. 2018). The work of Wu et al. (2019), demonstrates that transfersome
improves the stability, solubility, bioavailability, and safety of the antioxidant, resveratrol.
Resveratrol was able to penetrate the skin more easily after encapsulation. Therefore,
resveratrol transfersomes system could be considered as potential formulation in the
cosmetics, foods and drug industries (Wu et al. 2019).
Combination of polyphenolic phytoconstituents with phosphatidyl choline in certain
molar ratios yields a herbal drug delivery system, known as "Phytosomes"(Kondalkar and
Kondalkar, 2021). In other words, phytosomes are novel drug delivery systems developed to
incorporate standardized plant extracts into phospholipids to yield compatible lipid molecular
complexes that enhance absorption and bioavailability. Phytosomes also Herbosomes differ
from liposomes (Vaishnavi et al. 2021). Phytosomes have phytoconstituents and
phospholipids at the ratio of 1:1 or 1:2 ratio while in liposomes, several phosphatidyl choline
units surrounds the water-soluble constituents. As a result of this difference, phytosomes
achieve better absorption of drugs encapsulated in them better than liposomes which leads to
better bioavailability (Singh, 2018). Phytosomes enhance bioavailability, pharmacokinetic
and therapeutic profile of herbal drugs by improvingbthe capacity of the drugs to penetrate
rich lipid bio-membranes (Pradeep and Kumar, 2018). In a study by Sani et al. (2019),
phytosome complex containing cocoa pod extract was evaluated. The results show that the
phytosome-loaded cocoa pod extract had an encapsulation efficiency of 90.05%, a narrow
distribution size and 627 nm average globule size and. The formulation had high serum
penetrations and showed fine physical properties and chemical stability. Additionally the
serum has tyrosinase inhibitory and antioxidant properties equivalent to commercial product
(Priani et al. 2019).
Ethosomes are non-invasive drug carriers which enhance deep penetration of medicinal
products into skin layers and improve systemic circulation. They contain three major
constituents viz phospholipids, high ethanol concentrations, and deionized water. Ethosomes
are one of the major delivery systems utilized in topical herbal products as a result of the high
concentration of ethanol in them which makes them good for handling impairment in drug
permeation that is caused by lipid bilayers in the skin (Barani et al. 2021). In ethosome, the
phospholipids function as important vesicle forming component, while ethanol serves as skin
penetration enhancer to ease diffusion of drug through skin barrier. The preference of
ethosome by many researchers for studies of transdermal and topical drug delivery is due to
its several advantages which include enhanced permeation through skin, ability to achieve
smaller in size ranges, its non-toxic and non-invasive nature, and its ability to improved
stability, solubility and efficacy of many drugs (Sin and Kumar, 2019). According to Aniita et
al. (2020), ethosomal suspension from Spondia pinata bark extract can overcome the skin’s
barrier properties as opposed to extract solution. Also, the antimicrobial activity of the
ethosomal extract suspension was found to be similar to that of the extract solution (Alex et
al. 2020). An evaluation study of ethosomal gel preparation containing Achillea millefolium
revealed the possibility of obtaining a stable topical gel formulation from Achillea millefolium
extract. When compared to conventional gel, the Achillea millefolium extract increases drug
permeations in skin and promises a better product or new research works (Andleeb, 2021).

22 J. Onyebuchi Ogbodo, C. Precious Agbo, A. Chidiebere Echezona et al.

Conclusion

Phenolic compounds are the secret behind the use of herbal remedies for therapeutic
purposes. However, factor such as contaminants introduced during processing, unqualified
practitioners, substandard chemicals, and abnormal dosage delivery are some of the major
risk factors involved in using herbal medicine for the treatment of diseases. These challenges
can be by adherence to herbal regulatory model, use of efficient extraction methods, and
effective monitoring procedures on the use of adulterated synthetic ingredients in herbal
products, improve and harmonization of regulatory and monitoring bodies and the use of
nanocarriers (e.g., polymer nanoparticles, liposomes, polymeric conjugates and solid-lipid
nanoparticle o v d v y o d ug o h g og n

Re erence

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